rs12722477

chr6-29828599-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001384290.1(HLA-G):c.400C>A(p.Leu134Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,026 control chromosomes in the GnomAD database, including 12,937 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (1957 hom., cov: 32)
  • Exomes 𝑓: 0.10 (10980 hom.)
• Consequence: HLA-G NM_001384290.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.102

Genes affected

HLA-G (HGNC:4964): (major histocompatibility complex, class I, G) HLA-G belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-G is expressed on fetal derived placental cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exon 6 encodes the cytoplasmic tail. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060731173).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-G	NM_001384290.1	c.400C>A	p.Leu134Ile	missense_variant	3/7	ENST00000360323.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-G	ENST00000360323.11	c.400C>A	p.Leu134Ile	missense_variant	3/7		NM_001384290.1	P2

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22115 AN: 152090 Hom.: 1951 Cov.: 32

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.0870

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.0866

Gnomad OTH AF: 0.152

GnomAD3 exomes AF: 0.138 AC: 34138 AN: 247312 Hom.: 3010 AF XY: 0.136 AC XY: 18334 AN XY: 134724

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.178

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.296

Gnomad SAS exome AF: 0.185

Gnomad FIN exome AF: 0.0867

Gnomad NFE exome AF: 0.0861

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.103 AC: 150062 AN: 1460818 Hom.: 10980 Cov.: 53 AF XY: 0.105 AC XY: 75993 AN XY: 726732

Gnomad4 AFR exome AF: 0.230

Gnomad4 AMR exome AF: 0.178

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.381

Gnomad4 SAS exome AF: 0.182

Gnomad4 FIN exome AF: 0.0884

Gnomad4 NFE exome AF: 0.0790

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.145 AC: 22135 AN: 152208 Hom.: 1957 Cov.: 32 AF XY: 0.147 AC XY: 10970 AN XY: 74400

Gnomad4 AFR AF: 0.223

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.110

Gnomad4 EAS AF: 0.300

Gnomad4 SAS AF: 0.203

Gnomad4 FIN AF: 0.0870

Gnomad4 NFE AF: 0.0866

Gnomad4 OTH AF: 0.159

Alfa AF: 0.0557 Hom.: 607

Bravo AF: 0.155

TwinsUK AF: 0.0704 AC: 261

ALSPAC AF: 0.0804 AC: 310

ESP6500AA AF: 0.219 AC: 660

ESP6500EA AF: 0.0873 AC: 473

ExAC AF: 0.136 AC: 16442

Asia WGS AF: 0.324 AC: 1124 AN: 3478

EpiCase AF: 0.0950

EpiControl AF: 0.0991

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.46	T;T;.
MetaRNN	Benign	0.0061	T;T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.090
Sift	Uncertain	0.027	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.28	B;D;D
Vest4		0.032
MPC		1.4
ClinPred		0.076	T
GERP RS		0.56
Varity_R		0.29
gMVP		0.053

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12722477; hg19: chr6-29796376; COSMIC: COSV64405187; COSMIC: COSV64405187;